Compounds for the treatment of senile dementia

ABSTRACT

Azabicyclic compounds, processes for their preparation and their use in the treatment and/or prophylaxis of dementia in animals.

This invention relates to compounds having pharmaceutical activity, to aprocess for their preparation and their use as pharmaceuticals.

EP-0327155 discloses certain substituted pyrazines, pyrimidines andpyridazines useful in the treatment of senile dementia.

A novel group of compounds has now been discovered which enhanceacetylcholine function via an action at muscarinic receptors within thecentral nervous system and are therefore of potential use in thetreatment and/or prophylaxis of dementia in mammals.

According to the. present invention, there is provided a compound offormula (I) or a pharmaceutically acceptable salt thereof: ##STR1## inwhich one of X and Y represents hydrogen and the other represents Z,where Z is a group ##STR2## where R is selected from hydrogen, OR₁ , SR₁, N (R₁ )₂, NHCOR₁, NHCOOCH₃, NHCOOC₂ H₅, NHOR₁, NHNH₂, C₂₋₄ alkenyl,C₂₋₄ alkynyl, cyclopropyl or C₁₋₂ alkyl optionally substituted with OR₁,N(R₁)₂, SR₁, CO₂ R₁, CON(R₁)₂ or one, two or three halogen atoms, inwhich each R₁ is independently hydrogen or C₁₋₂ alkyl; r represents aninteger of 2 or 3, s represents an integer of 1 or 2 and t represents 0or 1, with the proviso that when Y is hydrogen s is 1.

Certain compounds of formula (I) are capable of existing in a number ofstereoisomeric forms including enantiomers. The invention extends toeach of these stereoisomeric forms, and to mixtures thereof (includingracemates). The different stereoisomeric forms may be separated one fromthe other by the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis.

In compounds of formula (I) having two assymmetric centres where Y isother than hydrogen, the stereochemical configuration in which the groupY and the (CH₂)s bridge are on the same side of the plane of themolecule which contains both bridgehead atoms and the ring carbon atombonded to the group Y will herein be referred to as the exoconfiguration. Similarly, the configuration of compounds in which thegroup Y and the bridge (CH₂)s are on opposite sides of theabove-mentioned plane of the molecule will herein be referred to as theendo configuration. Preferably compounds of formula (I) have the exoconfiguration. The compounds of formula (I) can form acid addition saltswith acids, such as the conventional pharmaceutically acceptable acids,for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric, oxalic andmethanesulphonic.

Preferred combinations of (r, s, t) include (2, 2, 0) , (3, 1, 0) , (2,1, 0) , (2, 1, 1) and (3, 1, 1) .

Preferably R₁ is hydrogen or methyl. Preferably R when C₁₋₂ alkyl isunsubstituted. Preferred values for R include hydrogen, C₁₋₂ alkyl,cyclopropyl, OR₁ , SR₁ or N (R₁ )₂.

Examples of R include hydrogen, methyl, ethyl, methoxy, methylthio,cyclopropyl, amino and dimethylamino.

R is preferably methyl or ethyl.

The invention also provides a process for the preparation of a compoundof formula (I), or a pharmaceutically acceptable salt thereof, whichprocess comprises:

(a) cyclising a compound of formula (II): ##STR3## in which (i) Arepresents Z or a group convertible thereto and B represents --(CH₂)_(j)L₁ where L₁ is a leaving group or A and L₁ together represent --COO--;one of j, k and l is 1 and the other two independently represent aninteger of 2 or 3, and R₅ represents hydrogen or an N-protecting group;to give a compound of formula (IIa): ##STR4## in which A' represents Zor a group convertible thereto, x-is an anion and the remainingvariables are as previously defined;

or (ii) A represents an electron withdrawing group, B representshydrogen and R₅ represents --(CH2)_(j) L₂ where L₂ is a leaving group;one of k and l is 1 and the other and j independently represent aninteger of 2 or 3; to give a compound of formula (IIb): ##STR5## inwhich K represents an electron withdrawing group or A' and the remainingvariables are as previously defined; and thereafter, optionally or asnecessary and in any appropriate order, removing any R₅ N-protectinggroup, converting K to A', converting A' to Z, optionallyinterconverting Z and/or forming a pharmaceutically acceptable salt; or

(b) cyclising a compound of formula (III): ##STR6## where R₅ is hydrogenor an N-protecting group, and either C is one, D is another and E is theremainder of --(CH₂)_(r) --, --(CH₂)_(s) -- and --(CH₂)_(t) --CHA'--CH₂-- or groups convertible thereto, A' is Z or a group convertible theretoand L₃ is a leaving group; or C is one and E is the other of --(CH₂)_(r)-- and --(CH₂)_(s) -- or groups convertible thereto and D represents--(CH₂)_(t) --CHA'--CH₂ -- where A' and L₃ together represent --COO--,and thereafter, optionally or as necessary and in any appropriate order,converting C, D and E to --(CH₂)_(r) --, --(CH₂)_(s) -- and --(CH₂)_(t)--CHA'--CH₂ --, removing any R₅ protecting group, converting A' to Z,optionally interconverting Z and/or forming a pharmaceuticallyacceptable salt; or

(c) cyclising a compound of formula (IV): ##STR7## where F is one and Gis the other of --(CH₂)_(r) -- and --(CH₂)₂ -- or groups convertiblethereto, and one of Y³ and Y⁴ is --(CH₂)_(u) --K and the other is--(CH₂)_(v) W or --(CH₂)_(v) L₄ where K and W are electron withdrawinggroups, L₄ is a leaving group, u is 1 or 2 and v is 0 or 1, with theprovisos that when Y⁴ is --(CH₂)_(v) W, v is 1, and Y⁴ is not--(CH₂)_(v) L₄, u and v being such that the desired compound of formula(I) is obtained, and thereafter, optionally or as necessary and in anyappropriate order, hydrolysing and decarboxylating the cyclisationproduct and converting the carbonyl group to CHA' where A' is Z or agroup convertible thereto, converting K to A' as defined, converting A'to Z, converting F and G to --(CH₂)_(r) -- and --(CH₂)_(s) -- asappropriate, interconverting Z and/or forming a pharmaceuticallyacceptable salt.

It will be appreciated that the product of process variant (a) is acompound of formula (I) in which variable Y is hydrogen and that theproduct of process variant (b) or (c) is a compound of formula (I) inwhich variable X is hydrogen.

In process variant (a), examples of the leaving groups L₁ and L₂ includehalo such as chloro or bromo, tosyloxy and mesyloxy.

Examples of R₅ when an N-protecting group include benzyl and substitutedbenzyl.

Examples of A and A' include hydroxy, alkoxycarbonyl, benzyloxycarbonyland cyano.

The cyclisation reaction is a nucleophilic substitution which may becarried out under conventional conditions appropriate to the groups Aand B. Thus, when B is (CH₂)_(j) Br and A is C₁₋₄ alkoxycarbonyl, thecyclisation is carried out in an inert solvent such as toluene or etherat elevated temperature. When B is (CH₂)_(j) OTos or (CH₂)_(j) O-Mes, itis preferably obtained by treatment of a (CH₂)_(j) OH group with asuitable reagent such as tosylchloride or mesyl chloride, in a base suchas pyridine, whereupon the cyclisation may proceed at ambienttemperature, or at elevated temperature in an inert solvent such astoluene. When A and L₁ together represent --COO--, the cyclisation maybe carried out in a lower alkanol such as ethanol in the presence ofacid such as hydrogen bromide. In the resulting compound of formula(IIa), A' will be an alkoxycarbonyl group corresponding to the loweralkanol used for the cyclisation.

Where R₅ is an N-protecting group such as benzyl, this may be removed byconventional hydrogenation, preferably catalytically over a suitablecatalyst such as Pd/C. Where A' or K is benzyloxycarbonyl,deesterification and deprotection may be effected simultaneously byconventional hydrogenation.

Examples of A when an electron withdrawing group include C₁₋₄alkoxycarbonyl and cyano.

When A is an electron withdrawing group such as C₁₋₄ alkoxycarbonyl, Bis hydrogen and R₅ is --(CH2)_(j) L₂ where L₂ is, for example, chloro,the cyclisation may be effected by treatment of the compound of formula(II) with lithium diisopropylamide.

In process variant (b), examples of leaving groups L₃ include halo suchas chloro, hydroxy and tosyloxy. In the group --(CH₂)_(t) --CHA'--CH₂--, examples of A' include hydroxy, cyano and formyl. In process variant(c), examples of L₄ include those given for L₃. Examples of electronwithdrawing groups K and W include C₁₋₄ alkoxycarbonyl and cyano.

In process variant (b) , where L₃ is hydroxy and D is --(CH₂)_(t)--CHOH--CH₂ --, the cyclisation of compounds of formula (III) may becarried out by pyrolysis, by the method of D. O. Spry and H. S. Aaron,J. Org. Chem., 1969, 34, 3674, to yield a compound where A' is hydroxy.

Where E is --(CH₂)_(t) --CO--CH₂ --, the cyclisation may be carried outunder basic conditions where R₅ is benzyl (F. I. Carrol, A. M. Ferguson,and J. B. Lewis, J. Org. Chem. 31, 2957, 1966).

Where L₃ and A' together represent --COO--, the cyclisation is arearrangement reaction which can be carried out under acid conditions ina polar solvent, such as hydrogen bromide in ethanol, at ambienttemperature, to yield a compound where A' is a carboxy ester group. Itis preferred to protect the nitrogen atom with an R₅ N-protecting groupsuch as benzyl, which may be subsequently removed by hydrogenation overa suitable catalyst such as Pd/C.

In process variant (c), where Y³ and Y⁴ both contain carboxy estergroups the cyclisation of compounds of formula (IV) is a Dieckmannreaction which is catalysed by a base such as potassium t-butoxide atelevated temperature in a solvent such as toluene.

The resulting β-keto ester is hydrolysed and decarboxylated underconventional conditions such as heating at reflux in dilute hydrochloricacid.

In process variant (c) where Y³ and Y⁴ both contain cyano groups thecyclisation of compounds of formula (IV) is a Thorpe reaction which iscatalysed by a base such as potassium t-butoxide at elevated temperaturein a solvent such as toluene.

The resulting β-keto nitrile is hydrolysed and decarboxylated underconventional conditions such as heating at reflux in dilute hydrochloricacid.

Where Y³ is --(CH₂)_(v) L₄, the cyclisation may be carried out asdescribed in EP-0094742 under basic conditions such as sodium hydrideand potassium t-butoxide, in an inert polar solvent such asdimethylformamide.

Conversions of the carbonyl group from process variants (b) and (c) andof groups A' and K, and interconversions of Z, may be carried outconventionally, see for example standard text books on heterocyclicchemistry such as `Comprehensive Heterocyclic Chemistry`, A. R.Katritzky and C. W. Rees, Pergamon, 1984.

The carbonyl group may be reacted with tosylmethyl isocyanide to yield acompound where A' is cyano.

The carbonyl group may be reduced to an A' hydroxy group with a suitablereducing agent such as sodium borohydride in ethanol at ambienttemperature, or sodium in ethanol at elevated temperature, such as theboiling point of the solvent, under an inert atmosphere such asnitrogen, depending on the stereochemistry required.

An A' hydroxy group may be converted to cyano by first converting it toa good leaving group such as mesyloxy or tosyloxy and then displacing itwith cyanide ion.

An A' hydroxy group may be oxidised to a carbonyl group by treatmentwith chromic acid or using dimethyl sulphoxide anddicyclohexylcarbodiimide.

The A' or K group is first converted, as necessary, to a suitablestarting group Z' for the chosen conversion reaction to give therequired group Z.

A Z' carboxy group may be obtained by conventional de-esterification ofan A' alkoxycarbonyl group.

A Z' chlorocarbonyl group may be obtained by treatment of a Z' carboxygroup with thionyl chloride at elevated temperature.

A Z' N-methoxy-N-methylcarboxamido group may be obtained by treatment ofa Z' chlorocarbonyl group with N,O-dimethyl hydroxylamine hydrochloridein the presence of pyridine in a suitable solvent such asdichloromethane.

A Z' aminocarbonyl group may be obtained by treatment of a Z'chlorocarbonyl group with ammonia.

A Z' cyano group may be obtained by treatment of a Z' aminocarbonylgroup with a dehydrating agent such as phosphorus pentoxide in toluene,or pyridine and trifluoroacetic anhydride.

A Z' CH₃ CO-- group may be obtained by treatment of a LiOOC group withmethyl lithium, the LiOOC group being obtained by hydrolysis of an A'alkoxycarbonyl group with lithium' hydroxide in water. Alternatively andpreferably, a Z' CH₃ CO-- group may be obtained by reaction of a Z'N-methoxy-N-methylcarboxamido group with methyl lithium. A Z' CH₃ CO--group may also be obtained by treatment of a cyano group with methyllithium.

A Z' bromomethylcarbonyl group may be obtained by treatment of a Z'COCH₃ group either with bromine in a suitable solvent such as methanol,the nitrogen of the azabicycle being protected as the hydrochloride orhydrobromide salt, or with lithium diisopropylamide and trimethylsilylchloride at low temperature followed by N-bromosuccinimide intetrahydrofuran at low temperature. Alternatively, a Z' --COCl group maybe converted to a --COCH₂ Br group by treatment with diazomethane inether at low temperature followed by hydrogen bromide in acetic acid atambient temperature.

A Z' --COCHO group may be obtained by treatment of a Z'bromomethylcarbonyl group with dimethylsulphoxide followed by heating atelevated temperature.

Alternatively, and the preferred route where compounds of formula (I) inwhich X is hydrogen are to be prepared, the required keto aldehydeintermediate may be generated in protected form via Pummererrearrangement of a precursor β-ketosulphoxide --COCH₂ SOR'(whereR'=alkyl or aryl). The ketosulphoxide can be reacted with a carboxylicacid anhydride, preferably trifluroacetic anhydride. The resulting ketoaldehyde protected as the α-trifluoroacetoxy sulphide can be convertedto the required triazine directly. The Pummerer rearrangement ofsulphoxides using trifluoroacetic anhydride has been described by H.Sugihara, R. Tanikaga and A. Kaji, Synthesis, 881 (1978). Alternativelythe Pummerer rearrangement can be carried out using an acid e.g.hydrochloric acid or trifluoroacetic acid. The resulting β-ketohemithioacetal can be deprotected to give the keto aldehyde intermediateusing reported procedures e.g. mercury (II) chloride or copper (II)chloride.

The β-ketosulphoxide intermediate may be prepared by treatment of a Z'N-methoxy-N-methylcarboxamido group with the anion derived from eithermethylphenylsulphoxide or dimethylsulphoxide. The anion can be generatedwith a base such as lithium diisopropylamine or n-butyllithium.

Alternatively the β-ketosulphoxide may be prepared by reacting theapproxiate sulphoxide with a carboxylic acid ester (A' =alkoxycarbonyl)in the presence of a base such as potassium t-butoxide.

The conversion of a Z'--COCHO group or protected form thereof to therequired 5-substituted-1,2,4-triazinyl group Z may be effected bytreatment with an appropriately substituted amidrazone RC(NH₂)=NNH₂according to the procedure described by H. Neunhoeffer et al.,Tetrahedron Lett., 1969 37 3147. The amidrazones are either knowncompounds or can be prepared via established routes. Formamidrazone canbe generated in situ and used without isolation as described by H.Neunhoeffer and F. Weischedel Liebigs Ann. Chem. 1971 749 16. Thereaction may be carried out in a suitable hydroxylic solvent such asmethanol or water. When an acid salt of the amidrazone, such as thehydrochloride salt, is used, it is necessary to add a base such aspyridine. Where the keto aldehyde is protected as the α-trifluoroacetoxysulphide the required triazine may be prepared directly by treating theα-trifluoroacetoxy sulphide with the appropriate amidrazone in thepresence of a base such as sodium bicarbonate. Where R is amino, thereagent is an aminoguanidine derivative such as the bicarbonate and thereaction is preferably carried out in aqueous medium at pH 4-7.Preparation of compounds where R ═S--R₁ may be achieved by reacting theketo aldhehyde or protected keto aldehyde with an appropriate S--R₁isothiosemicarbazide derivative such as S-methyl isothiosemicarbazidehydrogen iodide. Preparation of compounds where R═O--R₁ may preferablybe achieved by reacting a compound where R═S--R.sub. 1 with anappropriate alkoxide such as sodium methoxide in methanol at elevatedtemperature. Alternatively, preparation of compounds where R═O--R₁ canbe achieved by first hydrolysing a 3-amino triazine to give thecorresponding 3-keto triazine. The hydrolysis is carried out underalkaline conditions for example with potassium hydroxide. The 3-ketotriazine can be alkylated. For example methylation can then be achievedusing agents such as diazomethane. Alkylation usually gives rise to amixture of products from which the desired product of O-alkylation canbe separated. Compounds where R=amino or alkylamino may be prepared bytreating a compound where R =S--R₁ with ammonia, or the appropriatealkyl amine in a solvent such as ethanol.

Where applicable, an endo isomer may be obtained by epimerisation of acorresponding exo isomer or vice versa, the epimerisation reaction beingeffected by standard procedures at any convenient stage in the processbut preferably before the introduction of the group Y (J. Saunders etal., J. Chem. Soc. Chem. Comm. 1988 p 1618).

In a further aspect the invention provides a process for the preparationof a compound of formula (I), or a pharmaceutically acceptable saltthereof, which process comprises reacting a compound of formula (IVa):##STR8## in which r, s and t are as defined in formula (I), one of X'and Y' represents hydrogen and the other represents Z' wherein Z' is agroup convertible to Z as defined in formula (I), to convert Z' to Z andthereafter optionally forming a pharmaceutically acceptable salt.

Intermediates of formula (IVb) and salts thereof: ##STR9## in which r, sand t are defined in formula (I) , one of X" and Y" represents hydrogenand the other represents Z" where Z" is --COCHO or a protected formthereof are novel and form part of the invention.

Compounds of formula (II) may be prepared conventionally for example asdescribed in EP-0-287 356.

Where A is C₁₋₄ alkoxycarbonyl, B is (CH₂)_(j) L₁ and R₅ is hydrogen oran N-protecting group, the compound of formula (II) may be prepared bytreating a compound of formula (V): ##STR10## where R₆ is C₁₋₄ alkyl andthe remaining variables are as previously defined, with lithiumdiisopropylamide, prepared in situ from diisopropylamine andn-butyllithium followed by reaction with a compound L₅ (CH₂)_(j) L₁where L₅ is a leaving group, in an inert solvent such as ether atdepressed to elevated temperature. Both L₁ and L₅ are suitably bromo.

Where A and L₁ together represent --COO-- and j is 2, the compound offormula (II) may be prepared by reacting the compound of formula (V),treated with lithium diisopropylamide as before, with ethylene oxide inan inert solvent such as ether at depressed to elevated temperature.

Alternatively, the compound of formula (II) where A and L₁ togetherrepresent --COO, k is 2 and 1 is 1 may be prepared by a 1,3-dipolarcycloaddition reaction which involves reacting a compound of formula(VI): ##STR11## where n is 0 or 1, with a compound of formula (VII):##STR12## in which R₇ is an N-protecting group, in the presence of acatalytic amount of trifluoroacetic acid.

Where A is an electron withdrawing group such as C₁₋₄ alkoxycarbonyl, Bis hydrogen and R₅ is (CH₂ )_(j) L₂, the compound of formula (II) may beprepared by reacting the compound of formula (V) where R₅ is hydrogenwith a compound L₅ (CH₂)_(j) L₂ where L₅ is as previously defined, in asolvent such as acetone in the presence of a base such as potassiumcarbonate. The leaving group L₅ is preferably bromo and L₂ is preferablychloro.

Compounds of formulae (V) are known compounds or may be prepared byanalogous methods to those for preparing known compounds. The compoundof formula (V) where k is 2, 1 is 1 and R₅ is benzyl may be prepared bythe cyclisation of di-C₁₋₄ alkyl itaconate in the appropriate alkanolwith benzylamine at elevated temperature, followed by reduction of theresulting oxo group at the 2-position of the pyrrolidine ring with BH₃in tetrahydrofuran, at ambient to elevated temperature.

Alternatively, and preferably, a dipolar cycloaddition of a C₁₋₄alkylacrylate with a compound of formula (VII) in the presence of acatalytic amount of trifluoroacetic acid yields a compound of formula(V) directly.

Intermediates of formulae (III) and (IV) are known compounds (e.g. asdescribed in EP-A-0094742 or EP-A-0261763) or may be preparedanalogously.

Intermediates of formula (III) where A' and L₃ together represent--COO-- are described in, for example, Kuthan et al., Coll. Czechoslov.Chem. Comm., 1977, 42, 283 or may be prepared therefrom by conventionalhydrogenation of the pyridine ring over 5% Pt/C, and benzylation of thenitrogen atom by treatment with benzyl bromide and potassium carbonatein dry acetone.

Compound of formula (III) where A' and L₃ together represent --COO--,t=O, C is --CH₂ -- and E is --(CH₂)₂ -- or --(CH₂)₃ may be prepared by a1,3-dipolar cyclo addition reaction of a compound of formula (VII) with5, 6-dihydro-2H-pyran-2-one or 6,7-dihydro-5H-oxepin-2-one in thepresence of a catalytic amount of trifluoroacetic acid.

The use of an optical isomer of the compound of formula (III) or (VII)by providing a chiral centre in the N-protecting group R₅ or R₇respectively allows the isolation of a single enantiomer of the productof process variant (b) (ref. EP-0398616). Other routes for preparingsingle enantiomers are described in EP-0398617 and EP-0392803.

Intermediates of formula (III) where L₃ is a leaving group are describedin, for example, Spry et al., J. Org. Chem., 1969, 34, 3674 and Hasse etal., Chem. Ber., 1960, 93, 1686.

Intermediates of formula (IV) may be prepared from intermediates offormula (V) as described in, for example, Martell et al. , J. Pharm.Sci. , 1963, 52 (4) , 331, Sternbach et al. , J.A.C.S. , 1952, 74, 2215,Thill et al. , J. Org. Chem. , 1968, 33, 4376 and EP-0 094 742.

Compounds of formulae (VI) and (VII) may be prepared conventionally.Thus, a compound of formula (VI) may be obtained by the reaction ofγ-butyrolactone with ethyl formate in the presence of base such assodium hydride followed by reaction of the resulting formyl derivative(as the enol salt) with formaldehyde. A compound of formula (VII) may beobtained by the reaction of the primary amine R₇ NH₂ successively withchloromethyltrimethylsilane and formaldehyde followed by methanol andanhydrous potassium carbonate.

Pharmaceutically acceptable salts of the compounds of formula (I) may beformed conventionally by reaction with the appropriate acid such asdescribed above under formula (I) .

The compounds of the present invention enhance acetylcholine functionvia an action at muscarinic receptors within the central nervous systemand are therefore of potential use in the treatment and/or prophylaxisof dementia.

The present invention also provides a pharmaceutical composition, whichcomprises a compound of formula (I) or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, suppositories, reconstitutable powders, or liquidpreparations such as oral or sterile parenteral solutions orsuspensions.

In order to obtain consistency of administration it is preferred that acomposition of the invention is in the form of a unit dose.

Unit dose presentation forms for oral administration may be tablets andcapsules and may contain conventional excipients such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate. or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulphate.

The solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are of courseconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

Oral liquid preparations may be in the form of, for example, emulsions,syrups, or elixirs, or may be presented as a dry product forreconstitution with water or other suitable vehicle before use. Suchliquid preparations may contain conventional additives such assuspending agents, for example sorbitol, syrup, methyl cellulose,gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminiumstearate gel or hydrogenated edible fats; emulsifying agents, forexample lecithin, sorbitan monooleate or acacia; non-aqueous vehicles(which may include edible oils), for example almond oil, fractionatedcoconut oil, oily esters such as esters of glycerine, propylene glycol,or ethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid; and if desired conventional flavouringor colouring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, and, depending on theconcentration used, can be either suspended or dissolved in the vehicle.In preparing solutions the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, adjuvants such as a localanaesthetic, a preservative and buffering agents can be dissolved in thevehicle. To enhance the stability, the composition can be frozen afterfilling into the vial and the water removed under vacuum. Parenteralsuspensions are prepared in substantially the same manner, except thatthe compound is suspended in the vehicle instead of being dissolved, andsterilization cannot be accomplished by filtration. The compound can besterilized by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% to 99% by weight, preferably from10-60% by weight, of the active material, depending on the method ofadministration.

The invention also provides a method of treatment and/or prophylaxis ofdementia in mammals including humans, which comprises administering tothe sufferer an effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

The dose of the compound used in the treatment of such disorders willvary in the usual way with the seriousness of the disorders, the weightof the sufferer, and the relative efficacy of the compound. However, asa general guide suitable unit doses may be 0.05 to 100 mg. for example0.2 to 50 mg; and such unit doses may be administered more than once aday, for example two or three times a day, so that the total dailydosage is in the range of about 0.01 to 5 mg/kg; and such therapy mayextend for a number of weeks or months.

Within the above indicated dosage ranges no toxicological effects areindicated for the compounds of the invention.

In a further aspect the invention provides a compound of formula (I) ora pharmaceutically acceptable salt thereof for use as an activetherapeutic substance.

The invention further provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use in the treatmentand/or prophylaxis of dementia.

In another aspect the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof for thepreparation of a medicament for the treatment and/or prophylaxis ofdementia.

The following examples illustrate the invention.

Description 1 (±) 1( 1-Azabicyclo [2.2.2 ]oct-3-yl)-2-(phenylsulphinyl)ethanone (D1)

To a stirred solution of n-butyllithium (2.7 ml of a 1.6M solution inhexanes, 4.3 mmol) in dry tetrahydrofuran (5 ml) cooled to -78° C. undernitrogen was added dropwise a solution of diisopropylamine (0.44 g, 4.3mmol) in dry tetrahydrofuran (5 ml). The mixture was allowed to warm to-20° C., and was maintained at this temperature for 15 min. Aftercooling to -78° C. a solution of methyl phenyl sulphoxide (0.55 g, 3.9mmol) in dry tetrahydrofuran (2 ml) was added dropwise while maintainingthe temperature below -65° C. The reaction was stirred for a further 5rain and then a solution of (±) 1-azabicyclo[2.2.2]oct-3-yl-N-methyl-N-methoxycarboxamide (EP 322182, Description 22) (0.65g, 3.3 mmol) in dry tetrahydrofuran (5 ml) was added rapidly whileensuring that the temperature did not rise above -60° C. After stirringat -78° C. for 1 h, the reaction was allowed to warm to -30° C., andmaintained at this temperature for 30 min. The reaction was then pouredinto vigorously stirred orthophosphoric acid (20ml of a 5% H₃ PO₄solution) cooled below 0° C. The aqueous layer was separated, washedwith ether (3×20 ml) and then saturated with potassium carbonate. Afterextraction with chloroform (3×25 ml) the combined organic extracts weredried over sodium sulphate and concentrated in vacuo to give the titlecompound (D1) as an oil (1.0 g) consisting of a 1:1 mixture ofdiastereomeric keto sulphoxides. ¹ H NMR (CDCl₃) δ:

1.20-1.70 (8H, m) , 2.01 and 2.22 (each 1H, m) , 2.56-3.00 (12H, m) ,3.20 and 3.35 (each 1H, m) , 3.73 and 4.05 (each 1H, d, J=13.5 Hz), 3.88(2H, ABq, J=17 Hz), 7.50-7.76 (10H, m).

Description 2

(±) 1- (1-Azabicyclo[2.2.1 ]hept-3-yl) -2- (phenylsulphinyl) ethanone(D2)

(±) endo 1-Azabicyclo[2.2.1 ]hept-3-yl-N-methyl-N-methoxycarboxamide (EP402056, Description 36) was reacted with methyl phenyl sulphoxide usingthe procedure given in Description 1 to afford the title compound (D2)as a yellow solid (98%) which consisted of a mixture of 4 diastereomericketo sulphoxides.

¹ H NMR (CDCl₃) δ:

0.88-1.00, 1.08-1.27 and 1.28-1.70 (together 2H, each m) , 2.15-2.28 and2.32-3.15 (together 8H, each m) , 3.63-4.10 (2H, m) , 7.48-7.78 (5H, m).

Description 3 (3S, 4R)-1-Azabicyclo[2.2.1]hept-3-yl-N-methyl-N-methoxy-carboxamide (D3)

A stirred solution of ethyl (3S, 4R)-1-azabicylo[2.2.1]hept-3-ylcarboxylate (EP 0398616, Example 16) (10.5 g, 0.062 mol) in 8Mhydrochloric acid (150ml) was heated under reflux for 2.5 h, thenconcentrated in vacuo. The residue was twice treated with toluene (100ml) and concentrated to azeotrope out the remaining traces of water. Thewhite solid obtained was treated with thionyl chloride (100 ml) and themixture heated under reflux for 25 min to give a yellow solution. Thiswas concentrated in vacuo and the residue twice treated with toluene(100 ml) and concentrated to give the acid chloride hydrochloride saltas a beige solid. This product was dissolved in absolute chloroform (200ml) and the solution added over 20 min to a stirred solution of N,O-dimethylhydroxylamine hydrochloride (7.48 g, 0. 077 mol) and pyridine(24 ml, 0.29 mol) in absolute chloroform (200 ml) at --20° C. undernitrogen. The reaction mixture was allowed to warm to room temperatureover 1.5 h, then treated with saturated potassium carbonate solution andthe chloroform layer separated. The aqueous was extracted twice withchloroform (100 ml) and the three chloroform solutions combined, driedover sodium sulphate and concentrated in vacuo to leave a yellow oil.This was purified by passage through a short basic alumina columneluting with chloroform to give the title compound (D3) as a colourlessoil (10.6 g, 93%) . ¹ H, NMR (CDCl₃) δ:

1.35-1.47 (2H, m) , 2.44-2.52 (1H, m) , 2.58-2.74 (2H, m) , 2.76-2.94(3H, m) , 2.94-3.06 (1H, m) , 3.06-3.18 (1H, m), 3.22 (3H, s) , 3.72(3H, s) .

Description 4 (3R, 4R) and (3S, 4R) -1- (1-Azabicyclo[2.2.1]hept-3-yl)-2-(phenylsulphinyl) ethanone (D4)

(3S, 4R) -1-(1-Azabicyclo[2.2.1]hept-3-yl)-2-(phenylsulphinyl) ethanone(D4)

(3S, 4R)-1-Azabicyclo[2.2.1]hept-3-yl-N-methyl-N-methoxycarboxamide (D3)was reacted with methyl phenyl sulphoxide using the procedure given inDescription 1 to afford a yellow semi-solid (95%) containing a mixtureof the title compounds (D4).

¹ H NMR (CDCl₃) δ:

0.87-1.00, 1.07-1.27 and 1.32-1.70 (together 2H, each m) , 2.15-2.30 and2.35-3.15 (together 8H, each m) , 3.65-4.10 (2H, m) , 7.52-7.75 (5H, m).

EXAMPLE 1

(±) 5-(3-Methyl-l,2,4-triazin-5-yl)-1-azabicyclo[3.2.1]octane (E1)

A solution of 5- (α-bromoacetyl) -1-azabicyclo[3.2.1]octane hydrobromide(EP-0287356, Description 27) (0.5 g, 1.6 mmol) in dry dimethylsulphoxide(10 ml) was stirred overnight at 30° C. The reaction was concentratedunder high vacuum keeping the water bath temperature at 50°-60° C. Theresidue was placed in an oil bath at 125° C. for 4 min. A stream ofnitrogen was passed through the reaction vessel during this period, anddimethylsulphide was trapped in a solution of sodium hypochlorite. Theresulting (±) 2-oxo-2- (1-azabicyclo [3.2.1]oct-5-yl) ethanalhydrobromide was immediately treated with a solution of acetamidrazonehydrochloride* (0.18 g, 1.6 mmol) in methanol containing pyridine (0.31ml, 1.6 mmol). After stirring overnight at room temperature the reactionwas concentrated in vacuo. The residue was treated at ice temperaturewith a saturated solution of potassium carbonate (5 ml) and extractedinto chloroform (3×10 ml). After drying over sodium sulphate thecombined organic layers were concentrated in vacuo. Flash chromatographyon neutral alumina using 2% ethanol in chloroform as eluant afforded thetitle compound (El) (60 mg, 18%) which was converted into the oxalatesalt.

Oxalate salt:

¹ H NMR (d₆ -DMSO) δ: 1.70-2.45 (6H, m) , 2.76 (3H, s) , 3.15-3.65 (6H,m) , 9.45 (1H, s).

¹³ C. NMR (d₆ -DMSO) δ:

16.99, 23.45, 31.11, 33.56, 47.65, 49.96, 51.31, 58.63, 146.31, 162.50,164.69, 165.68

EXAMPLE 2 (±) 5-(3-Amino-l,2,4-triazin-5-yl)-1-azabicyclo[3.2.1]octane(E2)

(±) 5-(α-Bromoacetyl) -1-azabicyclo[3.2.11octane hydrobromide (1.0 g,3.2 mmol) was converted into (±) 2-oxo-2-(1-azabicyclo[3.2.1 ]oct-5-yl)ethanal hydrobromide as described in Example 1. The crude aldehyde wasimmediately treated with a suspension of aminoguanidine bicarbonate(0.46 g, 3.38 mmol) in water (15 ml) and the solution was acidified topH4 with 5M HCl. After stirring overnight at room temperature thereaction mixture was saturated with potassium carbonate then extractedinto chloroform. The combined organic extracts were dried over sodiumsulphate, concentrated in vacuo and the residue chromatographed onneutral alumina in a gradient of 0-8% methanol in chloroform. Thisafforded the title compound (E2) as a solid (95 mg, 15%) which wasconverted into the oxalate salt m.p. 184° C. (dec) (frommethanol-ether)..

Oxalate salt: .sup. 1H Nmr (d₆ -DMSO) δ: 1.92-2.56 (6H, m) , 3.34-3.80(6H, m) , 7.45 (2H, m) , 8.88 (1H, s) .sup. 13C Nmr (d₆ -DMSO) δ:

16.96, 31.06, 33.50, 47.37, 49.79, 51.25, 58.53, 138.35, 162.44, 162.91.

Analysis: C₁₂ H₁₇ N₅ O₄

requires: C, 48.81; H, 5.80; N, 23.72.

found: C, 48.44; H, 5.74; N, 23.57.

EXAMPLE 3 4-(3-Methyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane(E3)

A solution of 4-(α-bromoacetyl)-l-azabicyclo[2.2.1] heptane hydrobromide(EP-0366304, Description 19) (3.0 g, 10.0mmol) in dry dimethylsulphoxide(50 ml) was stirred overnight at room temperature. The reaction wasconcentrated in vacuo ensuring that the water bath temperature did notexceed 60° C. Co-distillation with successive portions of toluene wasused to remove residual dimethylsulphoxide. The residue was placed in anoil bath at 120° C. for 5 min. A stream of nitrogen was passed throughthe reaction vessel during this period, and the dimethylsulphide whichwas generated was trapped in a solution of sodium hypochlorite. Theresulting crude 2-oxo-2-(1-azabicyclo[2.2.1]hept-4-yl) ethanalhydrobromide was immediately treated with a solution of acetamidrazonehydrochloride (1.1 g, 10.0 mmol) in dry methanol (30 ml) containingpyridine (0.8 ml, 10.0 mmol). The mixture was stirred overnight at roomtemperature and then heated under reflux for 1 h. The reaction wasconcentrated in vacuo, and the residue was treated at ice temperaturewith a saturated solution of potassium carbonate (25 ml). Afterextraction with chloroform (3×25 ml) the combined organic layers weredried over sodium sulphate and concentrated in vacuo. The resultingcrude product was purified on a neutral alumina column using 1% ethanolin chloroform as eluant to give the title compound (E3) as an oil (0.63g, 33%) which was converted into the hydrochloride salt m.p. 222° C.(dec) (from methanol-ether) . Hydrochloride salt:

¹ H NMR (d₆ -DMSO) δ: 2.10-2.40 (4H, m) , 2.75 (3H, s) , 3.40-3.65 (6H,m) , 9.52 (1H, s).

¹³ H NMR (d₆ -DMSO) δ:

23.41, 31.87, 51.40, 52.25, 59.59, 146.66, 158.97, 165.86.

EXAMPLE 4 4-(3-Amino-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1 ]heptane(E4).

4-(α-bromoacetyl) -1 -azabicyclo[2.2.1 ]heptane hydrobromide(EP-0366304, Description 19) (0.5 g, 1.67 mmol) was converted into2-oxo-2- (1-azabicyclo [2.2.1]hept-4-yl)ethanal hydrobromide asdescribed in Example 3. The crude aldehyde was immediately treated witha suspension of aminoguanidine bicarbonate (0.25 g, 1.84 mmol) in water(10 ml) and the solution was acidified to pH6 with 5M hydrochloric acid.After stirring overnight at room temperature the reaction mixture wassaturated with potassium carbonate then extracted into chloroform (4×20ml). The combined organic extracts were dried over sodium sulphate andconcentrated in vacuo. The residue was crystallised fromisopropanolpentane to afford the title compound (E4) as a brown solid(0.14 g, 43%) . This was converted into the oxalate salt m.p. 178° C.(dec) (from methanol-ether).

Oxalate salt:

¹ H Nmr (d₆ -DMSO) δ: 2.10-2.38 (4H, m) , 3.37-3.65 (6H, m) , 7.37 (2H,s) , 8.83 (1H, s) .sup. 13C. Nmr (d₆ -DMSO) δ:

32.07, 51.41, 52.41, 59.69, 138.71, 159.55, 162.62.

Analysis: C₁₁ H₁₅ N₅ O₄

requires: C, 46.97; H, 5.38; N, 24.90

found: C, 46.61; H, 5.43; N, 24.58

EXAMPLE 5 4-(3-Methoxy-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1 ]heptane(E5)

A solution of 4-(3-Amino-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane(E4) (0.5 g, 2.6 mmol) in water (5 ml) was treated with potassiumhydroxide (0.29 g, 5.2 mmol) then heated at reflux for 7 h. A furtheraddition of potassium hydroxide (0.29 g) was made during this period.The reaction was concentrated in vacuo, dissolved in dry methanol (5 ml)then treated dropwise with methanolic hydrogen chloride to pH4. Thesolution was concentrated in vacuo and co-distilled with successiveportions of toluene to remove the last traces of solvent. The residuewas dissolved in dry dimethylsulphoxide (20 ml) and treated withdiazomethane (21 ml of a 0.635M solution in ether, 13.1 mmol) undernitrogen. After stirring at room temperature for 30 min the reaction wasacidified with acetic acid and concentrated in vacuo. The residue wastreated with saturated aqueous potassium carbonate (5 ml) and extractedinto chloroform (3×10 ml). The combined organic extracts were dried oversodium sulphate, and concentrated in vacuo. The residue waschromatographed on silica in a gradient of 0-5% methanol in chloroform.Pooling of pure fractions containing the faster running component of themixture afforded the title compound (E5) (23 mg) which was convertedinto the oxalate salt.

Oxalate salt:

¹ H NMR (d₆ -DMSO) δ: 2.08-2.39 (4H, m) , 3.34-3.66 (6H, m) , 4.11 (3H,s), 9.35 (1H, s).

¹³ C. NMR (d₆ -DMSO) δ:

31.96, 51.46, 52.45, 55.46, 59.77, 144.06, 162.10, 163.48

Observed mass=206.1167. Calculated mass for C₁₀ H₁₄ N₄ O=206.1172.

EXAMPLE 6 (±)3-(3-Amino-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.2 ]octane(E6)

(±) 3-(α-Bromoacetyl)-1-azabicyclo [2.2.2 ]octane hydrobromide(EP-0366304, Description 7) (1.0 g, 3.2 mmol) was converted into (±)2-oxo-2-(1-azabicyclo[2.2.2]octan-3-yl)ethanal hydrobromide using themethod described in Example 3. The crude aldehyde was immediatelytreated with a suspension of aminoguanidine bicarbonate (0.48 g, 3.5mmol) in water (10 ml), and the solution was acidified to pH4 with 5Mhydrochloric acid. The reaction mixture was stirred overnight at roomtemperature then heated under reflux for 1 h. It was then saturated withpotassium carbonate and extracted into chloroform (4×10 ml). Thecombined organic extracts were dried over sodium sulphate, concentratedin vacuo and the residue chromatographed on neutral alumina in agradient of 0-8% methanol in chloroform. This afforded the titlecompound (E6) as a colourless solid (42 mg, 6%) which was converted intothe oxalate salt m.p. 175° C. (dec) (from methanol - ether).

Oxalate salt: ¹ H Nmr (d₆ -DMSO) δ: 1.55-1.83 (2H, m) , 1.96-2.20 (2H,m) , 2.38-2.47 (1H, m) , 3.20-3.61 (6H, m) , 3.78-3.94 (1H, m) , 7.35(2H, m) , 8.76 (1H, s)

¹³ C. Nmr (d₆ -DMSO) δ:

18.06, 23.30, 24.90, 37.09, 45.21, 45.40, 46.46, 140.45, 161.05, 162.42

Analysis: C₁₀ H₁₅ N₅ 1.25 C₂ H₂ O₄

Requires: C,47.24; H, 5.55; N, 22.04

Found: C, 47.21; H, 5.64; N, 22.23

Example 7 (±) 3-(3-Methyl-1,2,4-triazin-5-yl)-1 -azabicyclo[2.2.2]octane (E7) Method A

(±) 3- (α-Bromoacetyl) -1-azabicyclo [2.2.2 ]octane hydrobromide(EP-0366304, Description 7) (0.5 g, 1.6 mmol) was converted into (±)2-oxo-2-(1-azabicyclo[2.2.2]octan-3-yl)ethanal hydrobromide using themethod described in Example 3. The crude aldehyde was immediatelytreated with a solution of acetamidrazone hydrochloride (0.18 g, 1.6mmol) in dry methanol (6 ml ) containing pyridine (0.13 ml, 1.6 mmol) .The mixture was stirred at room temperature for 48 h, and thenconcentrated in vacuo. The residue was treated with a saturated aqueoussolution of potassium carbonate (10 ml) and extracted into chloroform(4×10 ml). The combined organic layers were dried over sodium sulphateand concentrated in vacuo. The resulting crude oil was purified onneutral alumina using a graded eluant of 1-2% ethanol in chloroform togive the title compound (E7) as a yellow oil (16 mg, 5%).

¹ H NMR (CDCl₃) δ: 1.35 (1H, m) , 1.55 (1H, m) , 1.80 (2H, m) ,2.10 (1H,m), 2.75-3.10 (5H, m and 3H, s), 3.20 (1H, m), 3.55 (1H, dd, J=14 Hz, 5Hz) , 9.0 (1H, s).

Method B

A solution of (±) 1-(1-azabicyclo[2.2.21oct-3-yl)-2-(phenylsulphinyl)ethanone (D1) (1.0 g) in dry dichloromethane (15 ml) was cooled in iceunder nitrogen and treated dropwise with trifluoroacetic anhydride (0.93ml, 6.6 mmol) over a period of 5-10 min. After a further 45 min at icetemperature the reaction was concentrated in vacuo. Further drying underhigh vacuum produced a foam which was immediately treated with anaqueous solution (25 ml) containing acetamidrazone hydrochloride (0.72g, 6.6mmol) and sodium bicarbonate (1.1 g, 13.2 mmol). The mixture wasstirred vigorously at ice temperature for 30 min and then at roomtemperature for a further 6 h. The solution was saturated with potassiumcarbonate and extracted with chloroform (3×25 ml). The combined organicextracts were dried over sodium sulphate and concentrated in vacuo togive a gum. Purification by flash chromatography on neutral aluminausing a graded eluant of 1-3% methanol in chloroform afforded the titlecompound (E7) as a gummy solid (0.15 g) which was further purified byrecrystallisation of the oxalate salt m.p. 153-154° C. (fromacetone-methanol).

Oxalate salt: ¹ NMR (d₆ -DMSO) δ: 1.42-1.75 (2H, m), 1.87-2.14 (2H, m) ,2.40 (1H, m) , 2.78 (3H, s) , 3.10-3.35 (4H, m) , 3.50 (1H, m) , 3.60(1H, m) 3.80 (1H, m) 9.40 (1H, s) . ¹³ C. NMR (d₆ -DMSO) δ:

18.23, 23.75, 23.86, 25.46, 37.81, 45.55, 45.76, 46.96, 148.67, 161.29,165.08, 165.80.

EXAMPLE 8

(±) exo and endo 3-(3-Methyl-1,2,4-triazin-5-yl) -1-azabicyclo[2.2.1]heptane (E8a) and (E8b)

Method A

(±) exo and endo 3-(α-bromoacetyl) -1-azabicyclo [2.2.1]heptanehydrobromide (7:1 ratio of exo:endo isomers) (EP-0366304, Description23) (1.3 g, 4.35mmol) was converted into (±) exo and endo2-oxo-2-(1-azabicyclo[2.2.1]hept-3-yl)ethanal hydrobromide using themethod described in Example 3. The crude aldehyde was immediatelytreated with a solution of acetamidrazone hydrochloride (0.52 g, 4.75mmol) in dry methanol (15 ml) containing pyridine (0.6 ml). Afterstirring at room temperature for 4 days, the solvent was removed invacuo. The residue was treated with saturated aqueous potassiumcarbonate (15 ml) and extracted into chloroform (3×20 ml). The combinedorganic extracts were dried over sodium sulphate and concentrated invacuo. The residue was purified by repeated flash chromatography onsilica in a gradient of 0-10% methanol in chloroform. This afforded a7:1 mixture of the title compounds (E8a) and (E8b) as a gum (66mg, 8%)which was converted into the oxalate salt.

Oxalate salt: ¹ H NMR (d₆ -DMSO) : (Signals corresponding to major exoisomer) δ:

1.90 (1H, m), 2.15 (1H, m), 2.85 (3H, s), 3.12-4.09 (8H, m), 9.48 (1H,s).

Observed mass=190.1218. Calculated mass for C₁₀ H₁₄ N₄ =190.1219.

Method B

A solution of (±) 1- (1-azabicyclo[2.2.1]hept-3-yl)-2-(phenylsulphinyl)ethanone (D2) (0.779 g, 3.0 mmol) in drydichloromethane (20 ml) was cooled in ice and treated dropwise withtrifluoroacetic anhydride (0.85 ml, 6.0 mmol) . After stirring at icetemperature for a further 45 min the reaction was concentrated in vacuo.Following further drying under high vacuum the residue was treated withan aqueous solution (20 ml) containing acetamidrazone hydrochloride(0.66 g, 6.0 mmoles) and sodium bicarbonate (0.76 g, 9.0 mmol). Themixture was stirred overnight and then worked up as described in Example7 (Method B) to give a mixture of the title compounds (E8a) and (E8b)which was separated by flash chromatography on neutral alumina using agraded eluant of 1-1.5% methanol in chloroform. Pooling of purefractions containing the major faster running component afforded the exoisomer (E8a) as an oil (0.12 g, 21%) which was converted into theoxalate salt m.p. 135°-136.5° C. (from acetone-methanol).

Oxalate salt:

¹ H NMR (d₆ -DMSO) δ:

1.90 (1H, m), 2.15 (1H, m), 2.85 (3H, s), 3.08-3.90 (8H, overlapping m),9.48 (1H, s).

23.49, 27.44, 41.66, 43.51, 51.52, 54.87, 56.17, 148.25, 160.73, 164.59,165.60.

EXAMPLE 9

(±) exo and endo 3-(3-Amino-1,2, 4-triazin-5-yl) -1-azabicyclo[2.2.1]heptane (E9a) and (E9b) (±)1-(1-Azabicyclo[2.2.1 ]hept-3-yl)-2-(phenylsulphinyl) ethanone (D2) (0.5 g, 1.9 mmol) was treated withtrifluoroacetic anhydride as in Example 8 (Method B). The crude productwas treated with a suspension of aminoguanidine bicarbonate (0.52 g 3.8mmol) in water (15 ml). After stirring at room temperature overnight thesolution was cooled in ice, saturated with potassium carbonate andextracted into chloroform (3×15 ml). The combined organic extracts weredried over sodium sulphate, concentrated in vacuo then chromatographedon neutral alumina in a gradient of 0-4% ethanol in chloroform. Thisafforded a 3:1 mixture of the title compounds E9a and E9b as acolourless solid (51 mg, 14%) which was converted into the oxalate saltm.p. 162° C. (dec) (from methanol-ether) .

Oxalate salt:

¹ H NMR (d₆ -DMSO) (signals corresponding to major exo isomer) δ:

1.81-1.99 (1H, m), 2.05-2.21 (1H, m), 3.08-3.89 (8H, m), 7.34 (2H, br,s), 8.75 (1H, s).

¹³ C NMR (d₆ -DMSO) (signals corresponding to major exo isomer) δ:

27.32, 41.58, 43.05, 51.46, 54.63, 56.22, 140.36, 160.83, 162.55,164.36.

EXAMPLE 10

(±) exo and endo 3-(3-Ethyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane (E10a) and (E10b)

(±) 1- (1-azabicyclo[2.2.1]hept-3-yl) -2- (phenylsulphinyl) ethanone(D2) (0.79 g, 3.0retool) was treated with trifluoroacetic anhydride asdescribed in Example 8 (Method B). The crude product was treated with anaqueous solution (20 ml) containing propionamidrazone hydrochloride*(0.74 g, 6.0 mmol) and sodium bicarbonate (0.76 g, 9.0 mmol). Themixture was stirred at room temperature for 4 h and then worked up asdescribed in Example 7 (Method B). The crude product, consisting of a4:1 mixture of exo and endo isomers (E10a) and (E10b), was extractedinto ether and then purified by flash chromatography on silica using agraded eluant of 5-15% methanol in chloroform. Pooling of pure fractionscontaining the major faster running component afforded the exo isomer(E10a) as a pale yellow oil (90 mg, 15%).

¹ H NMR (CDCl₃) δ: 1.30-1.45 (3H, t, J =7Hz and 1H, m) , 1.72 (1H, m) ,2.40 (1H, m) , 2.55-2.72 (2H, m) , 2.80 (1H, m) , 2.88-3.05 (3H, m),3.11 (2H, q, J=7Hz), 3.25 (1H, m), 8.97 (1H, s).

¹³ C NMR (CDCl₃) δ:

12.35, 30.61, 30.65, 43.64, 47.16, 53.94, 58.32, 60.38, 147.49, 163.68,170.30.

Oxalate salt m.p. 73-75° C. (acetone-methanol) (hygroscopic).

EXAMPLE 11 (±) exo and endo 3-(3-Methylthio-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane (E11a) and (E11b)

(±) 1-(1-Azabicyclo[2.2.1]hept-3-yl) -2- (phenylsulphinyl) ethanone (D2)(0.79 g, 3.0 mmol) was reacted with trifluoroacetic anhydride asdescribed in Example 8 (Method B). The crude product was treated with anaqueous solution (20 ml) containing S-methylisothiosemicarbazidehydrogen iodide* (0.73 g, 3.0mmol) and sodium bicarbonate (0.5 g, 6.0mmol). The mixture was stirred at room temperature overnight and thenworked up as described in Example 7 (Method B). The crude productconsisting of a 4:1 mixture of exo and endo isomers (E11a) and (E11b)was purified by flash chromatography on silica using a graded eluant of5-10% methanol in chloroform. Pooling of pure fractions containing themajor faster running component afforded the exo isomer (E11a) as a paleyellow oil (0.15 g, 22%).

¹ H NMR (CDCL₃) δ: 1.27-1.40 (1H, m), 1.63-1.80 (1H, m), 2.40 (1H, m),2.55-2.68 (3H, s and 2H, m), 2.80 (1H, m), 2.85-3.02 (3H, m), 3.20 (1H,m), 8.80 (1H, s).

Hydrochloride salt m.p. 211°-212° C. (dec) (methanol-ether).

EXAMPLE 12 (±) exo and endo 3- (3-Methoxy-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane (E12a) and E(12b)

(±) exo and endo 3-(3-methylthio-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane (E11a) and (E11b) (4:1 mixture of exo andendo isomers) (60 mg, 0.27 mmol) was treated with sodium methoxide,generated from sodium (18 mg, 0.78 mmol) in dry methanol (7 ml). Themixture was heated under reflux for 4 h and then concentrated in vacuo.The residue was treated with a saturated solution of potassium carbonate(5 ml) and extracted into chloroform (3÷10 ml). The combined organiclayers were concentrated in vacuo to give a yellow oil (50 mg)consisting of a 4:1 mixture of the title compounds (E12a) and (E12b).Purification by chromatography as described in Example 11 afforded thetitle exo isomer (E12a) .

¹ H NMR (CDCl₃) δ:

1.30 (1H, m) , 1.70 (1H, m) , 2.40 (1H, m) , 2.50-2.70 (2H, m),2.80-3.03 (4H, m), 3.15 (1H, m), 4.18 (3H, s), 8.83 (1H, s).

EXAMPLE 13 3R, 4R) and (3S, 4R)3-(3-Ethyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane (E13a) and(E13b)

(3R, 4R) and (3S, 4R)1-(1-Azabicyclo[2.2.1]hept-3-yl)-2-(phenylsulphinyl) ethanone (D4) (2.0g, 7.6 mmol) was reacted with trifluoroacetic anhydride as described inExample 8 (Method B). The crude product was treated at ice temperaturewith an aqueous solution (50 ml) containing propionamidrazonehydrochloride (1.12 g, 9.1 mmol) and sodium bicarbonate (1.28 g,15.2mmol). The mixture was stirred at room temperature overnight andthen worked up as described in Example 7 (Method B). The product waspurified by chromatography on silica using 3% methanol in chloroform aseluant. The major component (E13a) was isolated as a pale yellow oil.

¹ H NMR (CDCl₃) δ:

1.29-1.47 (1H, m), 1.41 (3H, t, J=7Hz), 1.65-1.82 (1H, m), 2.37-2.45(1H, m) 2.54-2.74 (2H, m) , 2.77-2.83 (1H, m), 2.89-3.05 (3H, m), 3.12(2H, q, J=7Hz), 3.18-3.30 (1H, m), 8.98 (1H, s).

EXAMPLE 14 (±) exo and endo 3- (3-Dimethylamino-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane (E14a) and (E14b)

(±) exo and endo 3- (3-Methylthio-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane (E11a) and (E11b) (60 mg, 0.27 mmol) wastreated with dimethylamine (5 ml of a 33% solution in anhydrous ethanol)and the solution was heated under reflux for 8 h. During this period twofurther 5 ml aliquots of dimethylamine were added. The reaction wasconcentrated in vacuo to give a yellow oil containing the titlecompounds (E14a) and (E14b). Purification by chromatography as describedin Example 11 afforded the major exo isomer (E14a) .

¹ H NMR (CDCl₃) δ:

1.30 (1H, m), 1.68 (1H, m), 2.32-3.00 (7H, m) , 3.13-3.30 (1H, m and 6H,s), 8.39 (1H, s).

EXAMPLE 15 (±) exo and endo3-(3-Cyclopropyl-1,2,4-triazin-5-yl)-1-azabieyclo[2.2.1 ]heptane (E15a)and (E15b)

The title compounds (E15a) and (E15b) were prepared fromcyclopropanecarboxamide hydrazone hydrochloride* using the methoddescribed in Example 13. The crude product, consisting of a 4:1 mixtureof exo and endo isomers, was purified by chromatography on silica usinga graded eluant of 5-15% methanol in chloroform to give the title exoisomer (E15a) as a pale yellow oil.

¹ H NMR (CDCl₃) δ:

1.18 (4H, d, J =7Hz), 1.33 (1H, m), 1.70 (1H, m), 2.38 (1H, m), 2.47(1H, t, J=7Hz), 2.50-2.65 (2H, m) , 2.75 (1H, m) 2.85-3.00 (3H, m) 3.15(1H, m) 8.98 (1H, s).

EXAMPLE 16 (±) exo and endo 3- (1,2,4-Triazin-5-yl) -1-azabicyclo[2.2.1]heptane (E16a) and (E16b)

(±) 1- (1-Azabicyclo [2.2.1 ]hept-3-yl) -2- (phenylsulphinyl) ethanone(D2) (0.5 g, 1.9mmol) was treated with trifluoroacetic anhydride (0.8 g,3.8 mmol) as described in Example 8 (Method B). The resulting crudeproduct was dissolved in methanol (5 ml) and added to a solution offormamidrazone cooled to -78° C. The formamidrazone was generated fromanhydrous hydrazine (0.06 ml, 1.9 mmol) and formamidine hydrochloride(0.15 g, 1.9 mmol) in methanol (4 ml) following the procedure describedby Neunhoeffer and Weischedel*. The mixture was allowed to warm to roomtemperature overnight, and then concentrated in vacuo to give a crudegum containing the exo and endo isomers (E16a) and (E16b) in a ratio of4:1. Purification as described in Example 11 afforded the major exoisomer (E16a) as an oil (40 mg, 12%) .

¹ H NMR (CDCl₃) δ:

1.29-1.41 (1H, m), 1.66-1.81 (1H, m), 2.38-2.46 (1H, m, 2.53-3.06 (6H,m), 3.12-3.23 (1H, m), 9.16 (1H, d, J=3Hz ) , 9.55 (1H, d, J=3Hz ).

    ______________________________________                                                       R      r       s     .t                                        ______________________________________                                        Y=H      E1          CH.sub.3 3     1   0                                              E2          NH.sub.2 3     1   0                                              E3          CH.sub.3 2     1   0                                              E4          NH.sub.2 2     1   0                                              E5          OCH.sub.3                                                                              2     1   0                                     X=H      E6          NH.sub.2 2     2   0                                              E7          CH.sub.3 2     2   0                                              E8a (exo)   CH.sub.3 2     1   0                                              E8b (endo)  CH.sub.3 2     1   0                                              E9a (exo)   NH.sub.2 2     1   0                                              E9b (endo)  NH.sub.2 2     1   0                                              E10a(exo)   C.sub.2 H.sub.5                                                                        2     1   0                                              E10b(endo)  C.sub.2 H.sub.5                                                                        2     1   0                                              E11a(exo)   SCH.sub.3                                                                              2     1   0                                              E11b(endo)  SCH.sub.3                                                                              2     1   0                                              E12a(exo)   OCH.sub.3                                                                              2     1   0                                              E12b(endo)  OCH.sub.3                                                                              2     1   0                                              E13a(3R,4R) C.sub.2 H.sub.5                                                                        2     1   0                                              E13b(3S,4R) C.sub.2 H.sub.5                                                                        2     1   0                                              E14a(exo)   N(CH.sub.3).sub.2                                                                      2     1   0                                              E14b(endo)  N(CH.sub.3).sub.2                                                                      2     1   0                                              E15a(exo)   cC.sub.3 H.sub.5                                                                       2     1   0                                              E15b(endo)  cC.sub.3 H.sub.5                                                                       2     1   0                                              E16a(exo)   H        2     1   0                                              E16b(endo)  H        2     1   0                                     ______________________________________                                    

Biological Activity Radio ligand Binding

Cerebral cortex from Hooded Lister rats (Olac, UK) is homogenised in 2.5vols ice-cold 50 mM tris buffer pH 7.7 (at 25° C.). After centrifugationat 25,000×g at 4° C. for 15 min the pellet is resuspended in 2.5 volsbuffer and the wash repeated 3 times more. The final resuspension is in2.5 volumes and the homogenates are stored in 1 ml aliquots at -20° C.

Incubations (total volume 2 ml) are prepared using the above buffer withthe addition of 2 mM magnesium chloride in the 3H-Oxotremorine-M(3H-OXO-M) experiments. For 3H-Quinuclidinyl Benzilate (3H-QNB), 1 ml ofstored membranes is diluted to 30 ml and 0.1 ml mixed with test compoundand 0.27 nM (c. 25,000 cpm) 3H-QNB (Amersham International). For3H-OXO-M, 1 ml of membranes is diluted to 6 ml and 0.1 ml mixed withtest compound and 2 nM (c. 250,000 cpm) 3H-OXO-M (New England Nuclear).

Non-specific binding of 3H--QNB is defined using 1 μM Atropine sulphate(2 μM Atropine) and of 3H-OXO-M using 10 μM Oxotremorine. Non-specificbinding values typically are 5% and 25% of total binding, respectively.Incubations are carried out at 37° C. for 30 min and the samplesfiltered using Whatman GF/B filters. (In the 3H-OXO experiments thefilters are presoaked for 30 min in 0.05% polyethylenimine in water).Filters are washed with 3×4 ml ice-cold buffer. Radioactivity isassessed using a Packard BPLD scintillation counter, 3 ml Pico-Fluor 30(Packard) as scintillahr.

This test provides an indication of the muscarinic binding activity ofthe test compound. The results are obtained as IC₅₀ values (i.e. theconcentration which inhibits binding of the ligand by 50%) for thedisplacement of the muscarinic agonist 3H-OXO-M and the muscarinicantagonist 3H-QNB. The ratio IC₅₀ (3H-QNB)/IC₅₀ (3H-OXO-M) gives anindication f the agonist character of the compound. Agonists typicallyexhibit a large ratio; antagonists typically exhibit a ratio near tounity.

The results are shown in Table 1:

                  TABLE 1                                                         ______________________________________                                                      [.sup.3 H-OXO-M                                                                          .sup.3 H-QNB                                         Example       IC.sub.50  (nM)                                                                          IC.sub.50  (nM)                                      ______________________________________                                        E1            33         1800                                                 E2            5          1114                                                 E3*           70         4400                                                 E4            4          1494                                                 E5            1100       14000                                                E6            11         2366                                                 E7            3.3         175                                                 E8a           3.1         255                                                 E9a & E9b     1.1         320                                                 E10           68          240                                                 ______________________________________                                         *Tested as the hydrochloride salt. All other compounds were tested as         oxalate salts.                                                           

We claim:
 1. A compound of formula (I) or a pharmaceutically acceptablesalt thereof: ##STR13## in which one of X and Y represents hydrogen andthe other represents Z, where Z is a group ##STR14## where R is selectedfrom hydrogen, OR₁, SR₁, N(R₁)₂, NHCOR₁, NHCOOCH₃, NHCOOC₂ H₅, NHOR₁,NHNH₂, C₂₋₄ alkenyl, C₂₋₄ alkynyl, cyclopropyl or C₁₋₂ alkyl optionallysubstituted with OR₁, N(R₁)₂, SR₁, CO₂ R₁, CON(R₁)₂ or one, two or threehalogen atoms, in which each R₁ is independently hydrogen or C₁₋₂ alkyl;r represents an integer of 2 or 3, s represents an integer of 1 or 2 andt represents 0 or 1, with the proviso that when Y is hydrogen s is
 1. 2.A compound according to claim 1 wherein (r,s,t) is (2, 2, 0) , (3, 1, 0), (2, 1, 0) , (2, 1, 1) or (3, 1, 1).
 3. A compound according to claim 1wherein R is hydrogen, C₁₋₂ alkyl, cyclopropyl, OR₁, SR₁ or N (R₁ )₂. 4.A compound according to claim 3 wherein R₁ is hydrogen or methyl.
 5. Acompound according to claim 1 wherein R is hydrogen, methyl, methoxy,methylthio, cyclopropyl, amino or dimethylamino.
 6. (±) 5-(3-Methyl-1,2,4-triazin-5-yl) -1-azabicyclo [3.2.1]octane,(±)5-(3-amino-1,2,4-triazin-5-yl)-1-azabicyclo[3.2.1]octane, 4-(3-methyl-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane,4-(3-amino-1,2,4-triazin-5-yl) -1-azabicyclo [2.2.1]heptane,4-(3-methoxy-1,2,4-triazin-5-yl) -1-azabicyclo [2.2.1 ]heptane, (±)3-(3-amino-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.2 ]octane,(±)3-(3-methyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.2]octane, (±) exo3-(3-methyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane, (±) endo3-(3-methyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane, (±) exo3-(3-amino-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane, (±) endo3-(3-amino-1,2,4-triazin-5-yl)- 1 -azabicyclo [2.2.1 ]heptane, (±) exo3-(3-ethyl-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane, (±) endo3-(3-ethyl-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane, (±) exo3-(3-methylthio-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane, (±)endo 3-(3-methylthio-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1] heptane,(±) exo 3-(3-methoxy-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane,(±) endo 3-(3-methoxy-1,2,4-triazin,5-yl) -1-azabicyclo [2.2.1 ]heptane,(3R, 4R) 3-(3-ethyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane, (3S,4R) 3-(3-ethyl-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane, (±) exo3-(3-dimethylamino-1,2,4-triazin-5-yl)-1-azabicyclo [2.2.1 ]heptane, (±)endo 3-(3-dimethylamino-1,2,4-triazin-5-yl) -1-azabicyclo [2.2.1]heptane, (±) exo3-(3-cyclopropyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane, (±)endo 3-(3-cyclopropyl-1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane.(±) exo 3-(1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane or (±) endo3-(1,2,4-triazin-5-yl)-1-azabicyclo[2.2.1]heptane, or a pharmaceuticallyacceptable salt of any of the foregoing compounds.
 7. A process for thepreparation of a compound of formula (I) as defined in claim 1 or apharmaceutically acceptable salt thereof, which process comprisesreacting a compound of formula (IVa): ##STR15## in which r, s and t areas defined in formula (I), one of X' and Y' represents hydrogen and theother represents Z' wherein Z' is COCHO, optionally protected as theα-trifluoroacetoxy sulphide, to convert Z' to Z by treatment with anamidrazone RC(NH₂)=NNH₂ and thereafter optionally forming apharmaceutically acceptable salt.
 8. A pharmaceutical composition whichcomprises a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 9. A method of treatment and/or prophylaxis ofdementia in mammals including humans, which comprises administering tothe sufferer an effective amount of a compound according to claim 1.